Acute exposure of male Sprague-Dawley rats to either nicotine or tobacco smoke results in analgesia as measured by tail-flick latencies. A second treatment, 24 hr after the first, failed to produce analgesia, thereby demonstrating the rapid development of tolerance. The restraint which was a necessary part of the tobacco smoke exposure also produced analgesia, although of a more transient nature and lesser magnitude than that resulting from tobacco smoke exposure. Tolerance also developed to restraint stress-induced analgesia. The long-term (43 weeks) daily exposure of rats to tobacco smoke or restraint stress resulted in the development of cross-tolerance, suggesting that these two procedures share, at least in part, a common mechanism. Additionally, long-term tobacco smoke exposure resulted in an increased tail-flick latency when the animals had been withdrawn from tobacco smoke for 24 hr, suggesting the development of tolerance. The data also suggest a differential time course for the development of tolerance and dependence. This is the first report that addresses the effect of acute and chronic tobacco smoke exposure on pain sensitivity.